Diffusion Tensor Imaging of White Matter Change in AD. This Career Development application describes an integrated research and training period with two primary goals: (1) the development of the candidate into a strong and independent researcher in the study of the neuropathology of Alzheimer's disease (AD) through the application of advanced neuroimaging techniques and complementary neuropathology studies and (2) to determine the unique contribution of white matter (WM) degeneration in AD to the clinical profile of patients. The candidate is enthusiastic to continue AD-related research and to add new training to this research program. Immediate training goals will focus on three domains of study: (1) the application of novel neuroimaging data acquisition techniques to study neuropathology, (2) neuropathological assessment of AD and quantitative neuropathology techniques, and (3) advanced statistical analysis procedures for clinical research and multivariate data. The Mentors/Advisors on this proposal and the training environment of the Athinoula A. Martinos Center for Biomedical Imaging and the Massachusetts Alzheimer's Disease Research Center (MADRC) will assure superb instruction in the three fields. The candidate expects to apply the foundation in advanced imaging protocols and neuropathology of AD to develop a strong research program aimed at fully integrating these disparate domains to better understand AD pathophysioiogy. The proposed research will integrate novel diffusion tensor imaging (DTI) measures of WM microstructure with advanced methods for measuring morphological properties of gray matter to determine whether WM degeneration differs in AD compared to normal aging, and whether WM degeneration contributes to specific aspects of AD symptomology when controlling for gray matter degeneration. Patients will be recruited through the MADRC. Imaging data will be related to cognitive and clinical measures (including memory and dementia severity). The Specific Aims of this research are to: Aim 1. Identify differences in the patterns of WM degeneration in AD compared to normal aging. Aim 2. Identify the relation between WM degeneration and gray matter degeneration. Aim 3. Identify the unique contribution of WM degeneration to the patient's clinical profile. Thus, the proposed integrated training and research program could lead to novel insights about the unique contribution of WM degeneration to the clinical sequel of AD.